Intrascleral drug delivery device and associated methods

ABSTRACT

The present invention provides methods and devices for delivering an active agent into the eye of a subject. In one aspect, for example, the present invention provides an ocular drug delivery device including a housing configured to couple to the eye of the subject and a corneal seal coupled to the housing and positioned in the housing to encircle the cornea during use to form a corneal region, where the housing extends outward from the corneal seal to form a scleral region, and where the scleral region being positioned over the eye&#39;s sclera during use. The device further includes an active agent reservoir coupled to the housing and positioned to release active agent into the scleral region and a pressure regulator coupled to the housing that is operable to introduce negative pressure between the housing and the eye. Thus the corneal seal is operable to fluidically isolate the corneal region from the scleral region in response to the negative pressure.

PRIORITY DATA

This application is a continuation of U.S. patent application Ser. No.13/113,672, filed May 23, 2011, issued as U.S. Pat. No. 10,398,594,which is a continuation-in-part of U.S. patent application Ser. No.12/903,837, filed Oct. 13, 2010, which is a continuation of Ser. No.11/867,503, filed Oct. 4, 2007, issued as U.S. Pat. No. 8,480,638, eachof which is incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to systems, methods, and devices for thedelivery of an active agent through a region of a subject's oculartissue. Accordingly, the present invention involves the fields ofchemistry, pharmaceutical sciences, and medicine, particularlyophthalmology.

BACKGROUND OF THE INVENTION

Posterior and intermediate eye diseases that require ocular drugdelivery to prevent blindness include uveitis, bacterial and fungalendophthalmitis, age-related macular degeneration, viral retinitis, anddiabetic retinopathy, among others. For example, the reported incidenceof posterior uveitis is more than 100,000 people in the United States.If left untreated, uveitis leads to blindness. It is responsible forabout 10 percent of all visual impairment in the U.S. and is the thirdleading cause of blindness worldwide.

Treatments of intermediate and posterior uveitis are complicated by theinaccessibility of the posterior eye to topically applied medications.Current therapy for intermediate and posterior uveitis requires repeatedperiocular injections and/or high-dose systemic therapy withcorticosteroids. Injections are usually preferred to systemic drugadministration because the blood/retinal barrier impedes the passage ofmost drugs from the systemically circulating blood to the interior ofthe eye. Therefore large systemic doses are needed to treat intermediateand posterior uveitis, which often result in systemic toxicitiesincluding immunosuppression, adrenal suppression, ulcerogenesis, fluidand electrolyte imbalances, fat redistribution and psychologicaldisorders.

Endophthalmitis affects approximately 10,000 people in the United Stateseach year. Endophthalmitis is typically caused by gram-positive bacteriaafter ocular surgery or trauma, but it can also be fungal or viral innature. The current method of treating endophthalmitis is directinjection of antimicrobials into the vitreous. Intravitreal injectionsare necessary because periocular injections and systemic administrationdo not deliver efficacious amounts of antibiotics to the target sites inthe eye. Age-related macular degeneration (AMD) is the leading cause ofirreversible loss of central vision in patients over the age of 50. AMDaffects more than 15 million people worldwide.

Treatments of posterior eye diseases require intravitreal and periocularinjections or systemic drug administration. Systemic administration isusually not preferred because of the resulting systemic toxicity asdiscussed above. While intravitreal and periocular injections arepreferable to systemic administration, the half-life of most injectedcompounds in the vitreous is relatively short, usually on the scale ofjust a few hours. Therefore, intravitreal injections require frequentadministration. The repeated injections can cause pain, discomfort,intraocular pressure increases, intraocular bleeding, increased chancesfor infection, and the possibility of retinal detachment. The majorcomplication of periocular injections is accidental perforation of theglobe, which causes pain, retinal detachment, ocular hypertension, andintraocular hemorrhage. Other possible complications of periocularinjections include pain, central retinal artery/vein occlusion, andintraocular pressure increases. Therefore, these methods of ocular drugdelivery into the posterior of the eye have significant limitations andmajor drawbacks. In addition, injections are very poorly accepted bypatients. These methods also involve high healthcare cost due to theinvolvement of skilled and experienced physicians to perform theinjections.

Ocular iontophoresis is a noninvasive technique used to delivercompounds of interest into the interior of a patient's eye. In practice,two iontophoretic electrodes are used in order to complete an electricalcircuit. In traditional, transscleral iontophoresis, at least one of theelectrodes is considered to be an active iontophoretic electrode, whilethe other may be considered as a return, inactive, or indifferentelectrode. The active electrode is typically placed on an eye surface,and the return electrode is typically placed remote from the eye, forexample on the earlobe. The compound of interest is transported at theactive electrode across the tissue when a current is applied to theelectrodes. Compound transport may occur as a result of a directelectrical field effect (e.g., electrophoresis), an indirect electricalfield effect (e.g., electroosmosis), electrically induced pore ortransport pathway formation (electroporation), or a combination of anyof the foregoing.

One potential problem with present ocular iontophoretic methods anddevices concerns the actual delivery, or rather, the non-delivery of thedrug into the eye tissue. Because the return electrode is located remotefrom the eye, various conductive pathways may be formed. Such divergenceof the electric current will decrease the efficiency of drug delivery tothe target sites in the eye, and as a result, much of the drug may bedelivered into the tissues surrounding the eye rather than into the eyeper se.

Additionally, despite its apparent advantages, iontophoresis is reallyjust a method of limiting the invasiveness of drug delivery into theeye's interior. Once inside the eye, the pharmacokinetics of watersoluble compounds are identical to those following intravitrealinjections i.e. their half-lives are on the order of a few hours.Therefore, in many cases, traditional iontophoresis must be repeated asfrequently as intravitreal injections, leading to patient inconvenience,increased costs, and increased possibility of untoward effects caused bythe iontophoretic treatment itself.

The problem of patient compliance may be compounded by the need toreceive daily treatment in a medical facility with high healthcare costsand limited resources and practitioners for treating retinal diseases.Existing ocular iontophoresis systems are not patent-friendly, requiremultiple parts and assembly to practice, and include either clumsy orcomplicated procedures. As such, they require the involvement ofexperienced healthcare professionals to perform the treatments.Paraprofessional and/or in-home self administration use of such devicesare precluded by the technical complexity of many existing iontophoreticdevices, as well as the costs of expensive dose-controlling equipment.Individuals have a greater tendency to deviate from a medication regimenwhen required to leave home for medical treatment, particularly whensuch treatment is frequent.

SUMMARY OF THE INVENTION

The present invention provides methods and devices for the oculardelivering an active agent. In one aspect, for example, the presentinvention provides an ocular drug delivery device. Such a device caninclude a housing configured to couple to the eye of the subject and acorneal seal coupled to the housing and positioned in the housing toencircle the cornea during use to form a corneal region, where thehousing extends outward from the corneal seal to form a scleral region,and where the scleral region being positioned over the eye's scleraduring use. The device further includes an active agent reservoircoupled to the housing and positioned to release active agent into thescleral region and a pressure regulator coupled to the housing that isoperable to introduce negative pressure between the housing and the eye.Thus the corneal seal is operable to fluidically isolate the cornealregion from the scleral region in response to the negative pressure.Furthermore, the active agent reservoir can be utilized for passiveand/or active delivery.

Various pressure regulator configurations are contemplated, and any suchconfiguration that allows negative pressure to be introduced between theeye and the housing is considered to be within the present scope. In oneaspect, for example, the pressure regulator is also operable tointroduce positive pressure between the housing and the eye tofacilitate release of the housing from the eye. In another aspect, thepressure regulator is a vacuum bulb. In yet another aspect, the pressureregulator is removably coupled to the housing.

In one aspect, the device can include a scleral seal coupled to thehousing and positioned in the housing to encircle the corneal seal,where the scleral region is between the corneal seal and the scleralseal. In one specific aspect, the scleral seal is an outer edge of thehousing. In another specific aspect, the pressure regulator ispositioned in the housing to introduce the negative pressure into thescleral region.

In some aspects, the device can include a corneal cover coupled to thehousing and extending inward from the corneal seal to completely coverthe cornea during use. In one aspect, the pressure regulator ispositioned in the housing to introduce the negative pressure into thecorneal region.

The present invention additionally provides a method of limiting anactive agent from contacting an outer surface of a cornea of an eyeduring deliver of the active agent to a subject. Such a method caninclude applying a corneal seal to the eye at least substantiallyencircling the cornea to form a corneal region, where the corneal sealis coupled to a housing extending outward from the corneal seal over theeye's sclera to form a scleral region. The method also includes applyinga negative pressure between the housing and the eye to fluidicallyisolate the corneal region from the scleral region, and delivering anactive agent to the scleral region, whereby the active agent issubstantially precluded from the corneal region by the corneal seal. Inanother aspect, the method can include applying a scleral seal to theeye substantially encircling the corneal seal to form the scleralregion, wherein the corneal seal and the scleral seal are coupledtogether by the housing.

In one specific aspect, the negative pressure is applied between thehousing and the eye in the corneal region. In another specific aspect,the negative pressure is applied between the housing and the eye in thescleral region. In yet another specific aspect, the negative pressure isapplied between the housing and the eye in both the scleral region andthe corneal region. In some aspects the method can additionally includeapplying a positive pressure between the housing and the eye tofacilitate release of the housing from the eye.

The corneal seal can be positioned at various locations on the surfaceof the eye, provided that the cornea is at least substantially encircledthere within. In one aspect, the corneal seal is positioned around thecornea's periphery. In another aspect, the corneal seal is positioned toencircle the cornea at a distance of from about 0.01 mm to about 6.0 mmfrom the cornea's periphery. In yet another aspect, the corneal seal ispositioned to encircle the cornea at a distance of from about 0.01 mm toabout 2.0 mm from the cornea's periphery.

Various delivery modalities are also contemplated. For example, in oneaspect the active agent is delivered noninvasively. In a more specificaspect, the active agent is passively delivered. In another aspect, theactive agent is iontophoretically delivered.

The present invention additionally provides a method of delivering anactive agent to an eye of a subject while limiting the active agent fromcontacting an outer surface of a cornea during delivery. Such a methodcan include positioning a device as described herein on the eye of thesubject, applying negative pressure between the housing and the eye tofluidically isolate the corneal region from the scleral region, anddelivering an active agent to the scleral region, whereby the activeagent is substantially precluded from the corneal region by the cornealseal.

The particular active agent to be delivered may be a variety ofsubstances depending on the particular treatment to be effected. Suchsubstances may include drugs in various forms, including prodrugsthereof, and sustained release formulations, as required in order toprovide convenient and effective minimally invasive or non-invasivedelivery. Exemplary active agents are enumerated further herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross section view of an active agent delivery device inaccordance with an aspect of the present invention.

FIG. 2 is a cross section view of an active agent delivery device inaccordance with another aspect of the present invention.

FIG. 3 is a cross section view of an active agent delivery device inaccordance with yet another aspect of the present invention.

FIG. 4 is a cross section view of an active agent delivery device inaccordance with a further aspect of the present invention.

FIG. 5 is a top view of an active agent delivery device in accordancewith a further aspect of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Before the present devices and methods for ocular drug delivery aredisclosed and described, it is to be understood that this invention isnot limited to the particular process steps and materials disclosedherein, but is extended to equivalents thereof, as would be recognizedby those ordinarily skilled in the relevant arts. It should also beunderstood that terminology employed herein is used for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and, “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a polymer” includes reference to one or more ofsuch polymers, and “an excipient” includes reference to one or more ofsuch excipients.

Definitions

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set forthbelow.

As used herein, “formulation” and “composition” may be usedinterchangeably herein, and refer to a combination of two or moreelements, or substances. In some embodiments a composition may includean active agent, an excipient, or a carrier to enhance delivery or depotformation.

As used herein, “active agent” may be used to refer to an agent orsubstance that has measurable specified or selected physiologic activitywhen administered to a subject in a significant or effective amount. Itis to be understood that the term “drug” is expressly encompassed by thepresent definition as many drugs and prodrugs are known to have specificphysiologic activities. These terms of art are well-known in thepharmaceutical, and medicinal arts. Examples of drugs useful in thepresent invention include without limitation, steroids, antibacterials,antivirals, antifungals, antiprotozoals, antimetabolites,immunosuppressive agents, VEGF inhibitors, ICAM inhibitors, antibodies,protein kinase C inhibitors, chemotherapeutic agents, neuroprotectiveagents, nucleic acid derivatives, aptamers, proteins, enzymes, peptides,and polypeptides.

As used herein “prodrug” refers to a molecule that will convert into adrug (its commonly known pharmacological active form). Prodrugsthemselves can also be pharmacologically active, and therefore are alsoexpressly included within the definition of an “active agent” as recitedabove. For example, dexamethasone phosphate can be classified as aprodrug of dexamethasone, and triamcinolone acetonide phosphate can beclassified as a prodrug of triamcinolone acetonide.

As used herein, “effective amount,” and “sufficient amount” may be usedinterchangeably and refer to an amount of an ingredient which, whenincluded in a composition, is sufficient to achieve an intendedcompositional or physiological effect. Thus, a “therapeuticallyeffective amount” refers to a non-toxic, but sufficient amount of anactive agent, to achieve therapeutic results in treating a condition forwhich the active agent is known to be effective. It is understood thatvarious biological factors may affect the ability of a substance toperform its intended task. Therefore, an “effective amount” or a“therapeutically effective amount” may be dependent in some instances onsuch biological factors. Further, while the achievement of therapeuticeffects may be measured by a physician or other qualified medicalpersonnel using evaluations known in the art, it is recognized thatindividual variation and response to treatments may make the achievementof therapeutic effects a subjective decision. The determination of aneffective amount is well within the ordinary skill in the art ofpharmaceutical sciences and medicine. See, for example, Meiner andTonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographsin Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein byreference.

As used herein, “sclera” refers to the sclera tissue in the eye or theconjunctiva between the limbus and the fornix on the surface of the eye,which is the white part of the eye. In some aspects “sclera” can be usedin referring to other eye tissues.

As used herein, “eye” refers to the globe of the eye. As such, deliveryof an active agent into the eye refers to delivery of the active agentinto the globe of the eye itself.

As used herein, “subject” refers to a mammal that may benefit from theadministration of a composition or method as recited herein. Examples ofsubjects include humans, and may also include other animals such ashorses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals.

As used herein, “administration,” and “administering” refer to themanner in which an active agent, or composition containing such, ispresented to a subject. As discussed herein, the present invention isprimarily concerned with noninvasive delivery such as passive deliveryor iontophoretic delivery, especially with ocular delivery.

As used herein, “noninvasive” refers to a form of administration thatdoes not rupture or puncture a biological membrane or structure with amechanical means across which a drug or compound of interest is beingdelivered. A number of noninvasive delivery mechanisms are wellrecognized in the transdermal arts such as patches, and topicalformulations. Many of such formulations may employ a chemicalpenetration enhancer in order to facilitate non-invasive delivery of theactive agent. Additionally, other systems or devices that utilize anon-chemical mechanism for enhancing drug penetration, such asiontophoretic devices are also known. “Minimally invasive” refers to aform of administration that punctures a biological membrane or structurebut does not cause excessive discomfort to the subjects and severeadverse effects. Examples of “minimally invasive” drug delivery aremicroneedle, laser, or heat punctuation in transdermal delivery andperiocular injections in ocular delivery.

As used herein, the term “outward” refers to a direction extending awayfrom the center of the cornea. Thus extending “outward” from the cornealseal is intended to describe a region extending from the side of thecorneal seal opposite to the center of the cornea.

As used herein, “depot” refers to a temporary mass inside a biologicaltissue or system, which includes a drug that is released from the massover a period of time. In some aspects, a depot may be formed by theinteraction of an active agent with a depot forming agent, such as acomplexing ion which will form an active agent complex that is lesssoluble than the active agent by itself, and thus precipitate in-vivo.

As used herein, the term “body surface” refers to an outer tissuesurface of the subject such as tissue surfaces encountered in ocular andtransdermal delivery, or mucosal tissues lining a body cavity such asthe mouth for buccal delivery or vaginal tract for vaginal delivery. Theterm “skin” refers to an outer tissue surface of the subject. It istherefore intended that skin also refer to mucosal and epithelialtissues, as well as the outer surfaces of the eye.

As used herein, the terms “anode” and “cathode” refer to the electricalpolarity of an electrode. The terms “anode” and “cathode” are well knownin the art. It should be noted, however, that in some aspects thesedescriptive terms may be transitory. When using alternating current, forexample, two electrodes will alternate between anode and cathode as thecurrent alternates in electrical polarity.

As used herein, the term “reservoir” refers to a body, a lumen, or amass that may contain an active agent, a depot forming agent, secondarycompound, or other pharmaceutically useful compound or composition. Assuch, a reservoir may include any structure that may contain a liquid, agelatin, a semi-solid, a solid or any other form of active agent orsecondary compound known to one of ordinary skill in the art. In somecases, an electrode may be considered to be a reservoir.

As used herein, the term “contact lens” refers to a lens sized to fitapproximately over the cornea of the eye.

As used herein, the term “scleral lens” refers to a lens sized to coverand extend beyond the cornea across at least a portion of the sclera ofthe eye.

As used herein, the term “active electrode” refers to an electrodeutilized to iontophoretically deliver an active agent.

As used herein, the term “passive electrode” refers to an electrode thatis used to complete an electrical circuit without delivering a compoundor substance to a subject.

As used herein, the term “return electrode” refers to an electrodeutilized to complete an electrical circuit for active electrode. In oneaspect, a return electrode may be an active electrode used to deliver asecondary compound, such as an active agent, a depot forming agent, etc.In another aspect, a return electrode may be a passive electrode.

As used herein, the term “self-contained” refers to a device thatcontains therein, or substantially therein, all the components requiredfor use. For example, a self-contained iontophoretic device may containactive agents, reservoirs, electrodes, power supplies, etc., within asingle housing.

As used herein, the term “reacting” refers to any force, change inenvironmental conditions, presence or encounter of other chemical agent,etc. that alters the active agent. For example, “reacting” between theactive agent and the depot forming agent can be physical or chemicalinteractions.

As used herein, the term “precipitate” refers to anything less thanfully solubilized. As such, a precipitate can include not only crystals,but also gels, semi-solids, increased molecular weight, etc.

As used herein, the term “substantially” refers to the complete ornearly complete extent or degree of an action, characteristic, property,state, structure, item, or result. For example, an object that is“substantially” enclosed would mean that the object is either completelyenclosed or nearly completely enclosed. The exact allowable degree ofdeviation from absolute completeness may in some cases depend on thespecific context. However, generally speaking the nearness of completionwill be so as to have the same overall result as if absolute and totalcompletion were obtained. The use of “substantially” is equallyapplicable when used in a negative connotation to refer to the completeor near complete lack of an action, characteristic, property, state,structure, item, or result. For example, a composition that is“substantially free of” particles would either completely lackparticles, or so nearly completely lack particles that the effect wouldbe the same as if it completely lacked particles. In other words, acomposition that is “substantially free of” an ingredient or element maystill actually contain such item as long as there is no measurableeffect thereof.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint.

As used herein, a plurality of items, structural elements, compositionalelements, and/or materials may be presented in a common list forconvenience. However, these lists should be construed as though eachmember of the list is individually identified as a separate and uniquemember. Thus, no individual member of such list should be construed as ade facto equivalent of any other member of the same list solely based ontheir presentation in a common group without indications to thecontrary.

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited. Asan illustration, a numerical range of “about 1 to about 5” should beinterpreted to include not only the explicitly recited values of about 1to about 5, but also include individual values and sub-ranges within theindicated range. Thus, included in this numerical range are individualvalues such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4,and from 3-5, etc.

This same principle applies to ranges reciting only one numerical value.Furthermore, such an interpretation should apply regardless of thebreadth of the range or the characteristics being described.

The Invention

The present disclosure relates to devices for the delivery of an activeagent into the eye of a subject, including various methods associatedwith such devices. The inventors have discovered that ocular delivery ofan active agent can be facilitated and/or enhanced through the use of avacuum applied between the device and the surface of the eye. Thisvacuum force can function to improve contact between the device and theeye, isolate certain eye structures from contact with the active agent,and preclude contact between the active agent and lachrymal fluid, amongother things. By applying a vacuum force between the eye and the device,the device housing is brought into a more intimate contact with thesurface of the eye. Such an improved contact can have a variety ofbeneficial effects pertaining to ocular drug delivery, and such benefitscan vary depending on the design of the device and the location of thevacuum within the device and relative to the surface of the eye. Forexample, a vacuum between the device and the eye can cause a tightadherence there between. Such a tight adherence or “gripping” of the eyesurface by the device maintains the active agent reservoir at a distinctlocation with respect to the eye. In some cases, eye tissue associatedwith a reservoir can become “primed” and thus more readily pass activeagent there through. Accordingly, maintaining the reservoir at adistinct location can enhance active agent delivery. Additionally, inthose aspects where a drug depot is delivered into the eye, maintainingthe active agent and/or depot forming agent reservoir at a distinctlocation allows the formation of the depot at a correspondingly distinctlocation within the eye. Moving the reservoir(s) relative to the eyeduring delivery can cause a drug depot to form having a greater surfacearea than intended, and thus a greater active agent release from thedepot that expected.

As another example, when a housing is placed upon the eye, air pocketscan be present along the eye/device interface. This air can, in somecases, increase the required travel distance for an active agent to moveto and contact the eye surface during delivery. In addition toincreasing travel or diffusion distance, air situated between the eyeand the device can greatly slow or even halt the movement of the activeagent through the surrounding fluid. A vacuum force pulls the housingtoward the eye, thus displacing a portion of the fluid and/or thetrapped air. In those cases where the active agent is delivered from aportion of the housing subject to the vacuum, air pockets are eliminatedor substantially reduced by the vacuum, and thus increased mobility ofthe active agent is achieved. In those cases where the active agent isdelivered from a portion of the housing that is not subject to thevacuum (i.e. separated by a barrier structure), air pockets can be drawnto the vacuumed portion as the barrier seals and can be pressed from theinterface as the housing is pulled toward the eye.

The inventors have also discovered that ocular damage and/or sideeffects such as edema may occur when the cornea is exposed to variousactive agents and/or components of the active agent formulation atcertain (particularly high) concentrations. At lower concentrations ofthe active agent formulation, some irritation to the cornea or patientdiscomfort during treatment can occur, as the cornea is a highlysensitive tissue. As such, it can be beneficial to preclude exposure ofthese active agents and components to corneal tissues during drugdelivery. This can be accomplished by providing a seal between theactive agent reservoir and the cornea during use. The vacuum, whether itis applied at the cornea, at the active agent reservoir, or both, willfunction to seal the corneal region from contact with the active agentformulation. Additionally, in some cases direct physical contact betweenthe device and the cornea can cause damage and/or side effects. Thus insome aspects, sealing the device at the corneal seal can protect thecornea from physical contact, thus reducing the possibility of cornealdamage. Furthermore, when active agent delivery to posterior structuresof the eye are desired and thus delivery of the active agent through thesclera is desired, limiting active agent exposure to surface areas ofthe cornea can be beneficial.

Accordingly, in one aspect of the present invention, an ocular drugdelivery device is provided. As is shown in FIG. 1, such a device caninclude a housing 12 configured to couple to the eye of the subject, anda corneal seal 14 coupled to the housing and positioned in the housingto encircle the cornea 16 during use to form a corneal region 18. Thecorneal region 18 is thus an area that is sealed and prevented frombeing contacted by significant amounts of the active agent formulation.The housing 12 extends outward from the corneal seal 14 to form ascleral region 20, where the scleral region is positioned over the eye'ssclera 22 or conjunctiva during use. The device also includes an activeagent reservoir 24 coupled to the housing 12 and positioned to releaseactive agent into the scleral region 20, and a pressure regulator 26coupled to the housing 12 that is operable to introduce negativepressure (i.e. a vacuum) between the housing and the eye. The cornealseal 14 is operable to fluidically isolate or substantially fluidicallyisolate the corneal region 18 from the scleral region 20 in response tothe negative pressure. Additionally, as the negative pressure is appliedthe corneal seal provides an initial contact or gripping point thatfixed the position of the device as it seals. The location of thestrongest contact pressure will thus occur along the corneal seal. Thisis contrary to devices lacking such a corneal seal that can begin toseal in an arbitrary fashion, and thus may not adhere in the intendedposition. For configurations where the vacuum is applied at the centerof the cornea, designs lacking a corneal seal may begin to adhere fromthe periphery or a portion of the periphery inward in an arbitrarymanner. Designs having a corneal seal will grip the eye and adherearound the seal with a vacuum being formed within the sealed region in apredictable manner. As the seal is formed, air pockets are sucked fromthe corneal region into the pressure regulator as opposed to beingforced away from the pressure regulator due to the movement of thehousing in response to the negative pressure.

Various designs of corneal seals are contemplated, and any such designthat is capable of fluidically isolating or substantially fluidicallyisolating the corneal region from the scleral region is considered to bewithin the present scope. In one aspect, for example, the corneal sealis an annular or elliptical seal surrounding or substantiallysurrounding the cornea. The actual shape and/or geometry of the cornealseal can vary widely, and it should be understood that any corneal sealconfiguration that surrounds the cornea and provides fluidic isolationfrom the scleral region is considered to be within the present scope.The corneal seal can be a projection or extension of the housingmaterial, or it can be formed separately and attached thereto. Whenpositioning the device in the eye, the corneal seal can be initiallycontact the eye and allow for proper positioning prior to theintroduction of the negative pressure between the device and the eyesurface. Once the device has been positioned, the negative pressure canbe introduced to cause the housing to adhere to the surface of theeyeball, thus fluidically isolating the corneal region from the scleralregion.

The corneal seal is thus sized and positioned in the housing to encircleor substantially encircle the cornea during use. The corneal seal can besized and positioned at any location on the eye surface that allows thecornea to be encircled or substantially encircled, provided a sufficientscleral region is available from which to deliver the active agent. Inone aspect, the corneal seal is positioned around the cornea'speriphery. In another aspect, the corneal seal is positioned to encirclethe cornea at a distance of from about 0.01 mm to about 6.0 mm from thecornea's periphery. In yet another aspect, the corneal seal ispositioned to encircle the cornea at a distance of from about 0.01 mm toabout 2.0 mm from the cornea's periphery. Additionally, in one aspectthe corneal seal can be a circular or annular ring. In another aspect,the corneal seal can be an elliptical or semielliptical ring. It iscontemplated that the corneal seal can be of any shape or configurationthat limits or substantially limits contact between the cornea and theactive agent, and any such configuration or shape is considered to bewithin the present scope.

Numerous configurations of the housings of the devices of the presentinvention are contemplated, for both single-use and multiple-usedevices. In one aspect for example, the housing can be configured toallow the eyelids of the subject to close substantially completelythereover. In other words, when the device is in contact with the eye,the subject may be able to blink in a fairly normal fashion. In oneaspect, such a device can be configured to resemble a contact lens or ascleral lens. Additionally, for those aspects whereby the negativepressure is introduced into the corneal region, a portion of housing canbe disposed over the corneal region to provide the vacuum seal. Such acorneal cover can also extend the potential duration of drug delivery byprotecting the cornea from drying out and becoming uncomfortable for thesubject. In one aspect, the housing can be configured to conform to thesurface of the eyeball. Such a conformation in shape can facilitate thesealing of the corneal seal once the vacuum force is applied.

In another aspect, the housing can be configured to be substantiallyself-contained. Such a self-contained device would contain all thecomponents used in the delivery of the active agent into the eye. In thecase of iontophoretic delivery, for example, the power supply,electrodes, and conductive connections there between are contained inthe device. In this manner, the device allows simple insertion onto thesurface of the eye, and can facilitate substantially normal eye closureand blinking during use. This is particularly advantageous for oculariontophoresis as it provides an easy-to-use all-in-one device thatimproves patient compliance, especially, when multiple applications arerequired. In some aspects, the power supply can be located remotelyhowever.

Various materials are contemplated for use as the housing that cansecurely contain the various components of the device. In the case ofiontophoretic devices, the housing materials or at least a portion ofthe housing materials associated with the electrodes should havedielectric properties sufficient to maintain these components inelectrical isolation. It may be additionally beneficial to utilizematerials that provide some level of physical flexibility to avoiddamage or irritation to the eye surface. Any material having propertiesbeneficial to the construction of such a device would be considered tobe within the scope of the present invention. For example, the housingmaterial may include, without limitation, plastics, metals, composites,Teflon, nylons, polyesters, polyurethanes, polyethylenes,polycarbonates, and the like. Materials such as metals may be utilizedthat are conductive, and thus would need have dielectric materialsincorporated therein in order to maintain electrical isolation betweenvarious components of the device if used in an iontophoretic device.

The housing can also include a pressure regulator to create negativepressure between the device and the surface of the eye as has beendescribed. The negative pressure should be strong enough to hold thedevice in place during blinking. The negative pressure can be introducedin the corneal region, the scleral region, or in both the corneal andscleral regions. As is shown in FIG. 2, for example, the housing 30 caninclude a pressure regulator 32 associated therewith. In this aspect,the pressure regulator 32 is operable to deliver negative or positivepressure to the corneal space 34. Regardless of location, the pressureregulator can be of various configurations. For example, in one aspect,the pressure regulator can be a port or coupling for the attachment of apressure generating device such as a syringe (not shown). In anotheraspect, as is shown in FIG. 2, the pressure regulator 32 includes anattached pressure bulb 36 used to generate positive and negativepressure by squeezing. Thus by squeezing and releasing the bulb,negative pressure is introduced into the corneal region. Furthersqueezing of the bulb can generate positive pressure to allow release ofthe device from the eye. Thus in this case, the bulb can be made havingenough internal volume to seal the device with negative pressure andunseal the device following further squeezing. Whether or not a pressurebulb is used, the pressure regulator can be configured for use as ahandle to facilitate manipulation of the device before, during, andafter positioning on the eye. In some aspects, a flow regulator or valvecan be associated with the pressure regulator in order to control theflow of positive or negative pressure. In another aspect, the pressureregulator can be positioned in the housing at a location that isoff-center relative to the center of the cornea in order to allow thesubject to more easily blink or see through the device (not shown).

In various aspects of the present invention, a scleral seal can also bepositioned on the housing to provide a secondary seal. The scleral sealcan encircle the corneal seal and create a sealable scleral region therebetween into which the active agent can be delivered for subsequentmovement into the eye. This configuration can be beneficial for designswhere the scleral region is under negative pressure, or where it isdesirable to preclude lachrymal fluids from entering the scleral region.As such, the negative pressure can be applied between the housing andthe eye in the scleral region, the corneal region, or both. As is shownin FIG. 3, the device housing 40 includes a corneal seal 42 tofluidically separate the corneal region 44 from the scleral region 46,and a scleral seal 48 to further seal the scleral region 46. A pressureregulator 41 is shown for introducing negative pressure into the cornealregion 44. As with the corneal seal, the scleral seal can be an extendedor protruded section of the housing, or it can be a separate materialthat is subsequently associated with the housing. Thus active agent isreleased from the active agent reservoir 43 into the scleral region 46and maintained there during delivery into the eye. Additionally, in someaspects the scleral seal can be an outer edge of the housing, providedproper sealing can occur in response to negative pressure.

In another aspect, as is shown in FIG. 4, the housing 50 can include apressure regulator 51 operable to deliver negative or positive pressureto the scleral region 54. Other than the placement of the pressureregulator, FIG. 4 is similar in structure to FIG. 3. When negativepressure is applied to the scleral region, the housing is adhered to theeye surface and the corneal seal precludes contact between the activeagent formation and the cornea. In other aspects it is also contemplatedthat the pressure regulator can be at least partially coupled throughthe housing to both the scleral and corneal regions (not shown). In suchcases, the pressure regulator can be located anywhere on the housingwith pressure delivering channels connecting both corneal and scleralregions. It is also contemplated that a pressure regulator functionallycoupled to only the corneal region can be located in the housing overthe scleral region, and alternatively that a pressure regulatorfunctionally coupled to only the scleral region can be located in thehousing over the corneal region. Furthermore, in some aspects anadditional seal can be present to separate the negative pressureintroduced into the scleral region from the active agent reservoir.

As has been described, the device can be configured so as to minimizeobstructing the vision of a subject during active agent delivery. In oneaspect, as is shown in FIG. 5 for example, a device can have a housing60 and a corneal seal 62. One or more corneal seal extensions 64 can beextended away from the cornea for the inclusion of a pressure regulator66. In this way the pressure regulator 66 is positioned out of thevisual field of the subject, thus minimizing visual obstruction. Notethat the active agent reservoir(s) 68 are located in the housing 60 onthe outside of the corneal region 62, and are thus isolated from thecornea. It is also contemplated that a single corneal extension can beused, thus allowing a more continuous active agent reservoir surroundinga portion to substantially all of the corneal seal.

As has been described, at least one active agent reservoir is associatedwithin the housing in a position to deliver at least one active agentand in some cases at least one secondary compound such as a depotforming agent into the eye. The reservoirs according to aspects of thepresent invention are thus designed to hold an active agent or othersecondary compound prior to and during administration into the eye of asubject. In one aspect, a reservoir can be a distinct compartment,having a lumen for holding an active agent or other secondary compoundto be delivered. A reservoir can be a recessed portion of the housing, aseparate structure coupled to the housing, or any other reservoirconfiguration capable of containing an active agent or a secondarycompound. In some aspects, the reservoir can be located at a singlediscrete location in the housing. As one non-limiting example, thereservoir can be positioned in the housing to only contact the sclera inthe lower cul-de-sac of the eye. As another example, the reservoir canbe positioned in the housing to only contact the sclera in the uppercul-de-sac of the eye. In other aspects, the reservoir can be locatedacross a much broader area of the scleral region. In one non-limitingexample, the reservoir can be an annular ring that encircles orsubstantially encircles the cornea within the scleral region. In anotherexample, the reservoir can have an arc shape, and thus partiallyencircle the cornea in the scleral region. Such would be the case for anarc-shaped reservoir partially encircling the cornea within the lowercul-de-sac in the scleral region. Additionally, in one aspect the activeagent reservoir surface area can include substantially all of the areaof the scleral region. In another aspect, the active agent reservoir hasa surface area that is less than or equal to about 75% of the surfacearea of the scleral region. In yet another aspect, the active agentreservoir has a surface area that is less than or equal to about 50% ofthe surface area of the scleral region. In a further aspect, the activeagent reservoir has a surface area that is less than or equal to about25% of the surface area of the scleral region. In yet a further aspect,the active agent reservoir has a surface area that is less than or equalto about 10% of the surface area of the scleral region.

Additionally, such a reservoir can contain at least one access port toallow the reservoir to be filled, either before, during, or aftercontact with the eye surface of the subject. Such a configuration canallow the reservoir to be filled during use as the agent within isdepleted. In another aspect, a reservoir can be filled duringmanufacture of the device with an active agent or other secondarycompound to be delivered, particularly in those aspects where the deviceis intended for a single use. Various reservoir materials are known tothose skilled in the art, and all are considered to be within the scopeof the present invention. Additionally, the active agent or secondarycompound can be included in the reservoir in any form, including,without limitation, a liquid, gelatinous, semi-solid, or solid form. Inanother aspect the reservoir can consist of a portion of the activeelectrode, such that an active agent or secondary compound is deliveredfrom the electrode when electrical current is introduced.

The devices of the present invention, and thus the active agentreservoirs themselves, can be configured for active or passive delivery.Passive delivery of an active agent is accomplished by releasing theactive agent into the scleral region and allowing passive diffusion tomove the active agent into the eye. The active agent can be allowed tofreely diffuse throughout the scleral region, or it can be contained ina localized region in proximity to the reservoir. In some aspects theactive agent can be formulated for passive delivery using variouspermeation enhancers and/or passive delivery techniques. Further detailsregarding passive delivery can be found in U.S. patent application Ser.No. 11/999,266, filed on Dec. 3, 2007, which is incorporated herein byreference.

Active delivery of an active agent can be accomplished by a variety oftechniques, including, without limitation, iontophoresis, sonophoresis,and the like. In the case of iontophoresis, for example, the activeagent reservoir (and in some cases the secondary agent reservoir) isconfigured to receive electrical current from an active electrode tothus iontophoretically deliver an active agent or other compoundtherefrom. A return or inactive electrode is electrically coupled to thesubject to complete the electrical circuit. The return electrode can belocated either on the surface of the eye or at a location remote fromthe eye such as the earlobe. In some aspects, the return electrode canbe an “active” electrode and be associated with a reservoir to deliver asecondary agent or compound. In such cases, the return electrode and theassociated reservoir are likely situated on the surface of the eye.Further details regarding iontophoretic delivery can be found in U.S.patent application Ser. No. 11/414,134, filed on Apr. 27, 2006, which isincorporated herein by reference.

Various placement configurations of electrode/reservoir assemblies arecontemplated. For example, in many cases side-by-sideelectrode/reservoir assembly configurations may be beneficial. Such aconfiguration may allow effective iontophoresis at a target locationwhile minimizing the extent of the movement of the electrical current inother parts of the body. This is particularly beneficial whenadministering an active agent to sensitive areas such as the eye, wherepotential adverse effects may be caused by excessive electrical currentpassing through particularly sensitive tissues such as the retina in theback of the eye, the optic nerve, etc. Numerous placement configurationsare possible, and those discussed herein should not be seen as limiting.In one aspect the electrode/reservoir assemblies can be locatedside-by-side on the conjunctiva and sclera. In another aspect, oneelectrode/reservoir assembly may be located in the inferior cul-de-sacand the other electrode/reservoir assembly can be located in thesuperior cul-de-sac. The active agent can be delivered to various tissueregions depending on the relative locations of the electrode/reservoirassemblies, such as the sclera, conjunctival, subconjuctival space,ciliary body, choroids, retina, anterior chamber, vitreous, etc. Thepreferred site may depend on the site of drug action in the eye toprovide a pharmacological effect.

Prior methods of iontophoretic delivery of an active agent to the eyeoften locate return electrodes remote from the eye. While suchembodiments are considered to be within the scope of the presentinvention, such configurations are inconvenient and allow variousconductive pathways to be formed across the tissues surrounding the eyerather than focused only in the eye per se. Placing both the active andreturn electrodes in association with the surface of the eye canfacilitate the passage of electrical current transsclerally into the eyeunder the electrodes, particularly when current movement across thesurface of the eye is limited. In one aspect, the electrodes can berespectively configured on the surface of the eye such that anelectrical circuit is completed substantially within the eye of thesubject. In other words, the current between the electrodes passespredominantly through the eyeball tissues rather than into or throughthe connective tissues surrounding the eye. The active and returnelectrodes can directly contact the surface of the eye, or they cancontact the surface of the eye through an intermediate material orreservoir that is part of the device. In either case, such a “direct”contact between the electrodes and the eye surface may facilitate thefocusing of electrical current within the eye.

The relative spacing or the inter-electrode distance between theelectrodes can play an important role in determining where an activeagent is localized in the eye upon delivery. As such, in accordance withone aspect of the present invention, the electrodes can be spaced at aninter-electrode distance that controls the depth and extent ofpenetration of the active agent within the eye. Such a spacing can focusthe electric field more effectively within the eye, thus moreeffectively delivering the active agent. Increasing the inter-electrodedistance will generally cause current to flow deeper into the eye, thusiontophoretically delivering the active agent deeper. Smallinter-electrode distances will cause a more superficial delivery ofactive agent into the eye. Thus, by altering the physical locations ofeach of the electrodes relative to one another, and thus theinter-electrode distance between them, the active agent can be deliveredto particular regions of the eye at specific depths. As such, theinter-electrode distance may vary depending on the intended deliverylocation. In one aspect of the present invention, however, theinter-electrode distance may be less than about 40.0 mm. In yet anotheraspect, the inter-electrode distance may be from about 1 mm to about 10mm. In a further aspect, the inter-electrode distance may be from about0.3 mm to about 4 mm.

The active and return electrodes pass current due to a potentialdifference established there between by a power source. The current actsto move an active agent iontophoretically in a direction that isdependent on the charge characteristics of the active agent and thecharge orientation of the potential difference between the electrodes.An active electrode, whether it be an anode or a cathode, is designed todeliver electrical current across an associated reservoir toiontophoretically deliver the active agent located therein. As has beendescribed, in one aspect, one electrode can be an active electrode andthe other electrode can be a return electrode for merely completing theelectrical circuit. For example, the active electrode can be an anodeand the return electrode can be a cathode, or vice versa. In anotheraspect, one both the anode and the cathode can each have an associatedreservoir for the delivery of compounds. The compounds can be the sameor different, depending on the intended use and/or configuration of thedevice. In those aspects where the compounds are different, bothcompounds can be active agents, or one compound can be an active agentand one compound can be a secondary compound or agent that may or maynot have a direct therapeutic effect. One example of such a compound isa depot forming agent. The anode and the cathode can be of the same ordifferent size relative to each other. Also, the surface area of one orboth electrodes can be configured to modify their respective currentdensities when in use.

The present invention also includes methods that involve delivering anactive agent into the eye of a subject. In one aspect, for example, amethod of limiting an active agent from contacting an outer surface of acornea of an eye during delivery of the active agent to a subject isprovided. Such a method can include applying a corneal seal to the eyeat least substantially encircling the cornea to form a corneal region,wherein the corneal seal is coupled to a housing extending outward fromthe corneal seal over the eye's sclera to form a scleral region. Anegative pressure is applied between the housing and the eye tofluidically isolate the corneal region from the scleral region, and anactive agent is delivered to the scleral region. Thus the corneal sealsubstantially precludes the active agent from entering the cornealregion. In another aspect, the method can further include applying ascleral seal to the eye substantially encircling the corneal seal toform the scleral region, wherein the corneal seal and the scleral sealare coupled together by the housing. Such a method can be performed toadminister an active agent into the eye to treat various ocular and/orsystemic medical conditions.

Though numerous conditions would benefit from the methods and devices ofthe present invention, they are particularly well suited for thetreatment of ocular diseases such as direct, combinatory, and adjunctivetherapies. This is because of the relatively high permeability of theeye tissues and the large aqueous compartments in the eye. Examples ofeye diseases include without limitation, macular edema, age relatedmacular degeneration, anterior, intermediate, and posterior uveitis, HSVretinitis, diabetic retinopathy, bacterial, fungal, or viralendophthalmitis, eye cancers, glioblastomas, glaucoma, and glaucomatousdegradation of the optic nerve.

Accordingly, a wide range of active agents may be used in the presentinvention as will be recognized by those of ordinary skill in the art.In fact, any agent that may be beneficial to a subject when administeredocularly may be used. Examples of the active agents that may be used inthe treatment of various conditions include, without limitation,analeptic agents, analgesic agents, anesthetic agents, antiasthmaticagents, antiarthritic agents, anticancer agents, anticholinergic agents,anticonvulsant agents, antidepressant agents, antidiabetic agents,antidiarrheal agents, antiemetic agents, antihelminthic agents,antihistamines, antihyperlipidemic agents, antihypertensive agents,anti-infective agents, antiinflammatory agents, antimigraine agents,antineoplastic agents, antiparkinsonism drugs, antipruritic agents,antipsychotic agents, antipyretic agents, antispasmodic agents,antitubercular agents, antiulcer agents, antiviral agents, anxiolyticagents, appetite suppressants, attention deficit disorder and attentiondeficit hyperactivity disorder drugs, cardiovascular agents includingcalcium channel blockers, antianginal agents, central nervous system(“CNS”) agents, beta-blockers and antiarrhythmic agents, central nervoussystem stimulants, diuretics, genetic materials, hormonolytics,hypnotics, hypoglycemic agents, immunosuppressive agents, musclerelaxants, narcotic antagonists, nicotine, nutritional agents,parasympatholytics, peptide drugs, psychostimulants, sedatives,steroids, smoking cessation agents, sympathomimetics, tranquilizers,vasodilators, β-agonists, and tocolytic agents, and mixtures thereof.

Additionally, further examples of active agents may include steroids,aminosteroids, antibacterials, antivirals, antifungals, antiprotozoals,antimetabolites, VEGF inhibitors, ICAM inhibitors, antibodies, proteinkinase C inhibitors, chemotherapeutic agents, immunosuppressive agents,neuroprotective agents, analgesic agents, nucleic acid derivatives,aptamers, proteins, enzymes, peptides, polypeptides and mixturesthereof. Specific examples of useful antiviral active agents includeacyclovir or derivatives thereof.

Specific examples of active agents may also include hydromorphone,dexamethasone phosphate, amikacin, oligonucleotides, F_(ab) peptides,PEG-oligonucleotides, salicylate, tropicamide, methotrexate,5-fluorouracil, squalamine, triamcinolone acetonide, diclofenac,combretastatin A4, mycophenolate mofetil, mycophenolic acid, andmixtures thereof.

Under a number of circumstances, the active agent used may be a prodrug,or in prodrug form. Prodrugs for nearly any desired active agent will bereadily recognized by those of ordinary skill in the art. Additionally,prodrugs with high electromobility which metabolize into drugs with alow aqueous solubility may be beneficial. In this case, an electricallymobile prodrug of a low solubility drug in iontophoresis can be used tocreate a sustained release system in the eye. Because the prodrug hashigh electromobility, it is effectively delivered into the eye. Theprodrug then converts into the low solubility drug in the eye and theinsoluble drug precipitates in the eye. The drug in solid state in theeye will be slowly released into the eye and provide an ocular sustainedrelease condition.

Though any prodrug would be considered to be within the scope of thepresent invention, examples may include the derivatives of steroids,antibacterials, antivirals, antifungals, antiprotozoals,antimetabolites, VEGF inhibitors, ICAM inhibitors, antibodies, proteinkinase C inhibitors, chemotherapeutic agents, immunosuppressive agents,neuroprotective agents, analgesic agents, nucleic acid derivatives,aptamers, proteins, enzymes, peptides, polypeptides, and mixturesthereof. One specific example of a steroid derivative may includetriamcinolone acetonide phosphate or other derivatives of triamcinoloneacetonide, dexamethasone phosphate. For example, it may be preferable tolabel a steroid with one or more phosphate, sulfate, or carbonatefunctional groups, so the prodrug can be effectively delivered into theeye and form a complex with the precipitating ion.

In some cases, ocular treatment may be hampered by the in-vivomovement/clearance of the active agent in the eye. It is thereforecontemplated that various means for restricting or slowing such movementmay improve the effectiveness of the active agent therapy. In oneaspect, the in-vivo movement may be restricted by constriction of theblood vessels exiting an area in which the active agent is beingdelivered or precipitated. Such constriction may be induced by theadministration of a vasoconstricting agent. Such a vasoconstrictor maybe administered actively by iontophoretic or other means, or it may bedelivered passively. Specific non-limiting examples of vasoconstrictingagents may include α-agonists such as naphazoline, and tetrahydrozoline,sympathomimetics such as phenylethylamine, epinephrine, norepinephrine,dopamine, dobutamine, colterol, ethylnorepinephrine, isoproterenol,isoetharine, metaproterenol, terbutaline, metearaminol, phenylephrine,tyramine, hydroxyamphetamine, ritrodrine, prenalterol, methoxyamine,albuterol, amphetamine, methamphetamine, benzphetamine, ephedrine,phenylpropanolamine, methentermine, phentermine, fenfluramine,propylhexedrine, diethylpropion, phenmetrazine, and phendimetrazine.Vasocontricting agents can be administered either before or concurrentlywith the administration of the active agent. Though administration ofthe vasoconstrictor may occur following administration of the activeagent, the results may be less effective than prior or concurrentadministration. Additionally, in some aspects, the vasoconstrictingagent may have the same polarity as the active agent and administeredconcurrently with the active agent. Similarly, the vasoconstrictingagent may have the opposite polarity as active agent, and thus beadministered from a return electrode.

It may also be beneficial for the application site to be sealed with asealant following delivery of the active agent. This procedure mayprotect the tissue in which iontophoretic administration occurred.Sealants may include any known to one of ordinary skill in the art,including gels, glues and impermeable polymeric or resinous membranes.

Various treatment regimens according to aspects of the present inventionare contemplated. In one aspect, the administered active agent mayprovide an immediate therapeutic effect. In another aspect, the activeagent may provide a sustained therapeutic effect. In yet another aspect,the active agent may provide an immediate therapeutic effect and asustained therapeutic effect. In many cases, some form of sustainedrelease may be beneficial in order to reduce the frequency ofadministration. Such a reduction in administration may increase patientcompliance and reduce the frequency of eye infections and other relatedissues due to the decreased physical contact with the eye.

Various methods of providing sustained release, and therefore sustainedtherapeutic effect, are also contemplated, some of which have beendiscussed herein. Such a sustained release can be due to a property ofthe active agent, the use of a prodrug, the use of a sustained releasedepot, etc. In one aspect, a sustained release depot can be formed bythe reaction of an active agent with a depot forming agent in the eyetissue, following delivery of the active agent to the subject. The depotforming agent can be delivered to the subject, or it can be anendogenous substance that reacts with the active agent. In either case,the depot forming agent and the active agent do not interact with oneanother until the active agent is delivered into the subject. As such,in most cases the active agent and the depot forming agent will beseparated until both are located in-vivo. If the depot forming agent isto be delivered to the subject, then both agents should be deliveredseparately. Endogenous depot forming agents will, of course, not comeinto contact with the active agent until administration occurs. Thus anin-vivo reaction between the active agent and the depot forming agentwill cause the active agent or a derivative thereof to form a depot. Inone aspect such a depot forming mechanism may be a change in thesolubility of the active agent or a derivative of the active agent, thuscausing precipitation and subsequent depot formation. This depot ofactive agent complex is then able to deliver a therapeutic compound tothe biological system over time. Such sustained delivery can includelocal or systemic delivery of the active agent to the subject.

As a sustained release mechanism, it will be recognized that a depotformulation generally has an in-vivo solubility that is lower than thatof the active agent by itself. In this way, as the active agentdissolves out of the depot over time, a sustained therapeutic effect maybe obtained. Further, since the active agent in the depot is unable tohave a therapeutic effect until released therefrom, the solubilityproperties of the depot limit potential toxicity or overdose concernsthat would normally arise when delivering a sufficient amount of drug tolast over a prolonged period. Further details on such depotadministration and depot agents can be found in U.S. patent applicationSer. Nos. 11/238,144 and 11/238,104, both filed on Sep. 27, 2005, bothof which are incorporated herein by reference.

It should be understood that the above-described arrangements are onlyillustrative of the application of the principles of the presentinvention. Numerous modifications and alternative arrangements may bedevised by those skilled in the art without departing from the spiritand scope of the present invention. Thus, while the present inventionhas been described above with particularity and detail in connectionwith what is presently deemed to be the most practical and preferredembodiments of the invention, it will be apparent to those of ordinaryskill in the art that numerous modifications, including, but not limitedto, variations in size, materials, shape, form, function and manner ofoperation, assembly and use may be made without departing from theprinciples and concepts set forth herein.

What is claimed is:
 1. An ocular active agent delivery device,comprising: a housing including a corneal region and a scleral regionconfigured to couple to an eye of a subject; the corneal regioncomprising a corneal seal coupled to the housing and positioned in thehousing to encircle a cornea of the eye during use, and to form thecorneal region lacking a reservoir containing either an active agent orsecondary compound therein; the scleral region comprising at least oneactive agent reservoir positioned to release active agent into thescleral region, wherein the scleral region is configured to bepositioned over a sclera of the eye during use; and a pressure regulatorcoupled to the housing and operable to introduce negative pressurebetween the housing and the eye within the corneal region, wherein thecorneal seal is operable to fluidically isolate the corneal region fromthe scleral region in response to the negative pressure.
 2. The deviceof claim 1, wherein the pressure regulator is operable to introducepositive pressure between the housing and the corneal region of eye tofacilitate release of the housing from the eye.
 3. The device of claim1, wherein the pressure regulator is a vacuum bulb.
 4. The device ofclaim 1, wherein the pressure regulator is removably coupled to thehousing.
 5. The device of claim 1, further comprising a scleral sealcoupled to the housing and positioned in the housing to encircle thecorneal seal, the scleral region being between the corneal seal and thescleral seal.
 6. The device of claim 5, wherein the scleral seal has astructure that is operable to preclude lachrymal fluid from entering thescleral region.
 7. The device of claim 5, wherein the scleral seal is anouter edge of the housing.
 8. The device of claim 5, wherein thepressure regulator is positioned in the housing to introduce thenegative pressure into the scleral region.
 9. The device of claim 1,further comprising a corneal cover coupled to the housing and extendinginward from the corneal seal to completely cover the cornea during use.10. The device of claim 1, wherein the pressure regulator is positionedin the housing to introduce the negative pressure into the cornealregion.
 11. The device of claim 1, further comprising an anode and acathode both positioned to be facing the eye and at least one of theanode and cathode being in fluid communication with the active agentreservoir during use.
 12. The device of claim 11, wherein the anode andcathode are positioned so as to have an inter-electrode distance of fromabout 1 mm to about 10 mm.
 13. The device of claim 1, wherein thepressure regulator is oriented off-center from a center of the housingand in fluid communication with the corneal region.
 14. The device ofclaim 13, wherein negative pressure is applied between the housing andthe eye in the scleral region.
 15. The device of claim 1, wherein theactive agent reservoir has a surface area that is equal to 75% of thescleral region.
 16. The device of claim 1, wherein the active agentreservoir has a surface area that is equal to 10% of the scleral region.17. The device of claim 1, wherein the reservoir comprises an accessport to allow the reservoir to be filled.
 18. The device of claim 1,wherein the pressure regulator is coupled to a pressure deliveringchannel that is operatively coupled to the corneal region.
 19. Thedevice of claim 1, further comprising a power supply.
 20. A method ofdelivering an active agent to an eye of a subject while limiting theactive agent from contacting an outer surface of a cornea duringdelivery, comprising: positioning the device of claim 1 on the eye ofthe subject; applying negative pressure between the housing and the eyeto fluidically isolate the corneal region from the scleral region; anddelivering an active agent to the scleral region, such that the activeagent is substantially precluded from entering the corneal region by thecorneal seal.